Abstract
Thymic involution and proliferation of naive T cells both contribute to shaping the naive T-cell repertoire as humans age, but a clear understanding of the roles of each throughout a human life span has been difficult to determine. By measuring nuclear bomb test–derived 14C in genomic DNA, we determined the turnover rates of CD4+ and CD8+ naive T-cell populations and defined their dynamics in healthy individuals ranging from 20 to 65 years of age. We demonstrate that naive T-cell generation decreases with age because of a combination of declining peripheral division and thymic production during adulthood. Concomitant decline in T-cell loss compensates for decreased generation rates. We investigated putative mechanisms underlying age-related changes in homeostatic regulation of CD4+ naive T-cell turnover, using mass cytometry to profile candidate signaling pathways involved in T-cell activation and proliferation relative to CD31 expression, a marker of thymic proximity for the CD4+ naive T-cell population. We show that basal nuclear factor κB (NF-κB) phosphorylation positively correlated with CD31 expression and thus is decreased in peripherally expanded naive T-cell clones. Functionally, we found that NF-κB signaling was essential for naive T-cell proliferation to the homeostatic growth factor interleukin (IL)-7, and reduced NF-κB phosphorylation in CD4+CD31− naive T cells is linked to reduced homeostatic proliferation potential. Our results reveal an age-related decline in naive T-cell turnover as a putative regulator of naive T-cell diversity and identify a molecular pathway that restricts proliferation of peripherally expanded naive T-cell clones that accumulate with age.
Highlights
Naive T-cell numbers and clonal diversity represent the adaptive immune system’s potential to sense and respond to foreign pathogens and mutant proteins expressed by malignant cells [1, 2]
After red blood cell lysis, total white blood cell samples were subjected to a pan-naive T-cell isolation by magnetic beads followed by fluorescence-activated cell sorting (FACS) purification of CD45RA+CCR7+ CD4+CD31+, CD31−, or CD8+ T cells (Fig 1C, S1 Table)
For CD8+ naive T cells, we included a subset of donors, which were collected early in our analysis using CD45RA+CD62L+CD3+CD8+ as a purification criteria after we concluded that the inclusion of these samples did not impact our downstream results (S1 and S2 Tables)
Summary
Naive T-cell numbers and clonal diversity represent the adaptive immune system’s potential to sense and respond to foreign pathogens and mutant proteins expressed by malignant cells [1, 2]. Loss of thymic output in adults shifts the responsibility for the maintenance of naive T-cell numbers to peripheral division of existing clones rather than de novo production of new, unique clones [8]. In theory, this should lead to a gradual loss of naive T-cell diversity, as individual clones compete for space and limited homeostatic growth factors, such as interleukin (IL)-7, in the peripheral lymphoid tissues [9, 10]. A dramatic loss of diversity has been observed in a fraction of elderly individuals, which has led to speculation that a sudden collapse of naive T-cell diversity may be causally linked to immune dysfunction associated with advanced age [10, 11]
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